The Unfolded Protein Response (UPR) is a cellular homeostatic program initiated by an excess of unfolded/misfolded client proteins in the Endoplasmic Reticulum (ER) lumen, with primarily a cytoprotective effect. We previously showed that tumor cell survival under hypoxic and nutrient deprivation stress is dependent on the ER resident protein and UPR effector PERK. In addition to the tumor microenvironment, oncogenes are also known to activate cellular stress responses, including metabolic stress, apoptosis, and senescence. MYC is the target of chromosomal translocation or gene amplification during the development of many human cancers. c-Myc expression has been associated with robust upregulation of both total cellular protein content and rates of protein synthesis. This finding raises the possibility that c-Myc-transformed cells experience a higher than normal level of ER stress. In preliminary studies, we have used multiple genetic models of regulated c-Myc activation, to demonstrate that Myc activates the PERK/elF2a/Atf4 arm of the UPR. Activation of the UPR leads to increased cell survival via the induction of cytoprotective autophagy and reduced release of Ca^* from the ER. PERK ablation significantly reduced Myc-induced autophagy, cell transformation and tumor formation in nude mice. Samples from E)j,-Myc mice and human lymphomas demonstrate higher levels of UPR activation, compared to corresponding normal tissues. We hvpothesize that the increase in protein burden in cells overexpressing c-Myc results in ER stress and activation of the UPR which tempers ER stress and facilitates transformation and tumor growth. This hypothesis will be tested in four specific aims: In Aim 1, we will determine the requirement for elF2a phosphorylation, ATF4 and Chop induction, Nrf2 activation and miRNA 211 in c-Myc-induced transformation in vitro and in vivo. In specific Aim 2, we will elucidate the mechanism of cytoprotection afforded by UPR activation in the context of oncogenic transformation by Myc. Under specific Aim 3, we will investigate the impact of c-Myc overexpression on the activation of the other two major UPR pathways. In specific Aim 4, we will determine the role of PERK activation in c-Myc induced lymphomagenesis using a transgenic mouse model. Successful completion of these studies would establish, for the first time, Myc upregulation as a cell-autonomous activator of UPR and would unveil novel targets for inhibiting Myc-dependent tumorigenesis. RELEVANCE (See instructions): The major oncogene c-Myc is activated in malignancies, including lymphomas, colorectal cancer and neuroblastomas. The Unfolded Protein Response (UPR) is increasingly been recognized as a mechanism of tumor resistance to stress and- promoter of tumorigenesis. Our preliminary findings suggest a novel role of UPR activation as an enhancer of tumorigenesis by c-Myc. Our proposed studies will investigate the mechanism of UPR activation by Myc in cell lines, animal tumor models and human samples and have the potential to lead to the development of novel therapeutics targeting Myc-dependent malignancies.